Biologically active implants

ABSTRACT

This invention relates to an implant for treating pathological changes in the spinal column and/or locomotor system. According to one embodiment of the invention, the implant has a surface, a body, and an enamel-like or varnish-like coating that is up to 100 μm thick, comprises a biodegradable polymer such as polylactide which has a mean molecular weight of 100 kDa or less, forms an adhesive bond to the surface of the body such that when the implant is implanted, mechanical friction will not abrade or damage the coating, and is adapted to contact bone when implanted. This coating has an osteoinductive effect, which promotes the healing of fractures. Additional osteoinductive materials such as growth factors may be incorporated in the coating. The invention also relates to a method for producing such an implant using the following steps: preparing a dispersion of a biodegradable polymer in an organic solvent; applying the dispersion on the surface to be coated; and allowing the organic solvent to evaporate.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.09/801,752, filed Mar. 9, 2001 now U.S. Pat. No. 6,998,134, which is acontinuation of the U.S. National Stage designation of InternationalPatent Application No. PCT/EP99/06708, filed Sep. 10, 1999, published inEnglish as WO 00/15273, which claims priority to German Application No.198 43 251.8, filed Sep. 11, 1998. The entire contents of theseapplications are expressly incorporated herein by reference thereto.

FIELD OF THE INVENTION

The present invention relates to an implant designed to compensate forpathological changes or conditions in the spinal column and/or locomotorsystem. The invention also covers a method for producing such animplant.

BACKGROUND OF THE INVENTION

Implants for treatment of pathological conditions of the spine and/orlocomotor system are known in the prior art. They are intended, forexample, to mechanically stabilize a fracture, thus promoting thehealing process or, in the case of endoprosthetic implants, to bepermanently bonded to the bone.

PCT Publication No. WO 98/19699 describes the systemic administration ofmedications or hormones serving to promote osteosynthesis and thus toaccelerate the healing process of the fracture. Examples of suitablemeans include growth factors such as IGF-I. Such systemic applications,however, can lead to undesirable side effects.

PCT Publication No. WO 93/20859 describes the fabrication of a thin foilor film consisting of a polylactic-acid/polyglycol-acid copolymercontaining growth factors. The intent is to wrap a foil of that type,for instance, around fracture-fixation devices prior to theirimplantation. This is supposed to release the growth factors inlocalized fashion in the area of the fracture. In practice, however,this method is unsuitable since, for instance, a nail wrapped with afoil of that type cannot be inserted in the medulla in a way that thefoil, which only loosely envelops the nail, actually reaches the pointof its intended healing action.

In light of the foregoing, a need exists for an implant that promotesthe healing process in pathological changes of the spinal column andlocomotor system, especially by furthering osteosynthesis, and thusaccelerating the healing of fractures or the integration of an implant.

SUMMARY OF THE INVENTION

The present invention relates to an implant for treating and/orcompensating pathological changes or conditions in the spinal columnand/or locomotor system. The implant, in various embodiments, has avarnish-like biodegradable polymer coating of a thickness of 100 μm orless, a thickness of 50 μm or less, preferably 30 μm or less, and moredesirably, 20 μm or less. In other embodiments, the varnish-like coatinghas a thickness of 10 to 30 μm, and preferably 10 to 20 μm. The implantcan be a fracture-fixation device or an endoprosthetic device. Examplesof such devices include plates, screws, nails, pins, wires, threads, orcages used for the spinal column and locomotor system.

The polymer used for the coating may have a glass transition temperatureof 37° C. (98.6° F.) or higher and a mean molecular weight of 100 kDa orless. Examples of suitable polymers include poly-α hydroxy acids,polyglycols, polytyrosine carbonates, starch, gelatins, and cellulose,as well as blends and interpolymers thereof. Examples of suitable poly-αhydroxy acids include polylactides, polyglycol acids, and interpolymersthereof. In one embodiment, the coating contains at least two layers ofthe biodegradable polymer.

The varnish-like coating according to the present invention can alsoinclude pharmaceutically active additives, such as osteoinductivesubstances. Examples of such substances include one or more growthfactors. Specifically, the growth factors can be selected from the groupconsisting of IGF, TGF, FGF, EGF, BMP, and PDGF. In an exemplaryembodiment, the coating contains IGF-I, TGF-β, or combinations thereof.In one embodiment, the growth-factor percentage of the total weight ofthe coating is 0.1 to 10% by weight, preferably 0.5 to 8% by weight and,more desirably, 1 to 5% by weight. In a specific embodiment, the coatingcontains about 5% by weight of IGF-I and about 1% by weight of TGF-β.

The present invention also relates to a method of producing an implanthaving a varnish-like biodegradable polymer coating of a thickness of100 μm or less. Furthermore, the invention relates to an implantproduced by such a method. The method for producing an implant includesthe following steps: preparing a dispersion of the biodegradable polymerin an organic solvent; applying the dispersion on the surface to becoated; and allowing the solvent to evaporate. The application andevaporation processes may occur, for example, at a temperature ofbetween 0 and 30° C. (32-86° F.), and preferably at about 22° C. (72°F.). Additionally, the evaporation of the solvent may occur, forexample, in a gaseous atmosphere substantially saturated with solventvapor. In an exemplary embodiment, the application of the dispersion andthe evaporation of the solvent are repeated two or more times.

The dispersion may be a colloidal solution of the polymer in thesolvent. Such a colloidal solution may be produced by allowing a mixtureof polymer and solvent to stand for periods of time ranging from 1minute to 24 hours, preferably 2 to 24 hours, 3 to 12 hours, or 4 to 8hours, and most preferably for about 6 hours. The colloidal solution maybe filtered prior to its application. The filtering may occur through amicropore filter with a pore size of 0.45 μm or smaller.

Suitable solvents include ethyl acetate or chloroform with thedispersion containing, for example, 20 to 300 mg of polymer per ml ofsolvent.

In one embodiment, the present invention relates to an orthopaedicimplant having a varnish-like biodegradable polymer coating of athickness of 100 μm or less, the implant being made by the followingsteps:

-   -   a. Preparing a dispersion of the biodegradable polymer in an        organic solvent;    -   b. Applying the dispersion on the implant surface to be coated;        and    -   c. Allowing the solvent to evaporate.

BRIEF DESCRIPTION OF THE DRAWINGS

Preferred features of the present invention are disclosed in theaccompanying drawings, wherein similar reference characters denotesimilar elements throughout the several views, and wherein:

FIG. 1 shows the degradation of a polylactide coating on an implantaccording to the present invention as a function of time both in vivoand in vitro;

FIG. 2 shows the release of growth factors contained in the polylactidecoating as a function of time;

FIG. 3 shows a radiographic comparison of the effect of implants havinga coating according to the present invention versus untreated (uncoated)implants on fracture healing in rats;

FIG. 4 shows a biomechanical comparison of the implants of FIG. 3;

FIG. 5 shows a histomorphometric comparison of the implants of FIG. 3;

FIG. 6 shows illustrations of histomorphometric examinations;

FIG. 7 shows a radiographic comparison between coated and uncoatedimplants in Yucatan pigs;

FIG. 8 is a biomechanical comparison of the implants of FIG. 7; and

FIG. 9 shows the maximum torsional load and torsional stiffness inanother examination of tibia fractures in rats.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention relates to an implant having a varnish-likecoating of a biodegradable or resorbable polymer that may be up to 100μm thick. As used herein, the term implant refers to a device, which inthe process of a surgical procedure is at least partially introducedinside the body. In an exemplary embodiment, the present invention isdirected to implants of the type that serve to support a pathologicallychanged spinal column and/or locomotor system, especially by providing amechanical reinforcement. The pathological changes may be in the form offractures, pathological changes of joints and bones, distended or tornligaments or tendons and the like. Application of the implants mayinvolve direct contact with, attachment to or insertion in a bone ofother part or element of the spinal column or locomotor system (such asligaments or tendons).

The term implant is to be understood in the broadest sense of the wordsince it also includes, for instance, implants which are used forelongative or reductive ostectomies, craniotomies, for ligament healingand restoration, for tumor and sports-injury-related surgery, indentistry as well as in the case of oral, maxillary and facialdislocations.

The term fracture fixation device refers to any device that serves tofix, correct and/or mechanically stabilize a fractured bone. Examplesthereof include plates, screws, nails, pins, wires, sutures, or cagesfor the spinal column and locomotor system. Usually, fracture fixationdevices are removed after the fracture has healed, but in certaincircumstances, they may be permanently left in or on the bone or theycan be reabsorbed by the organism. Endoprosthetic implants are designedto permanently remain in the body and usually function as substitutesfor a natural body part such as a joint, a bone section or a tooth.

The implants according to one embodiment of the invention are made of abase material that is chemically and/or physically different from thatof the varnish-like coating. In many cases, the base material may not bebiodegradable. This implies that under physiological conditions, wherethe implant is used and for the length of time during which it istypically retained in the body, the base material will not decay,corrode or in any other way change its physiochemical state, or if itdoes, then only with negligible deterioration of its desired effect. Animplant according to one aspect of the invention will in many casesconsist of a metal or an alloy such as stainless steel and/or titanium.Alternatively, the implant may consist of a base material which isitself biodegradable or bioresorbable.

In accordance with the present invention, the implants are provided witha varnish-like coating. The term varnish-like means that the coatingbonds with the surface of the base material with enough adhesivestrength such that, when the implant is implanted, mechanical frictionwill not abrade or otherwise damage the coating, or at least, not tosuch an extent as to compromise its physical effect, as described inmore detail further below. For example, it is advantageous to properlydrive a nail, provided with the varnish-like coating, into the bonewithout any significant abrasion of the varnish-like coating.

The coating may be up to 100 μm thick. In other words, it is preferablethat the average thickness of the coating is 100 μm or less. Forexample, spots with a thickness of more than 100 μm, occasioned byfluctuations in the coating process, would be allowed.

The coating consists of a biodegradable polymer. This means that, due toits exposure to the physiological conditions prevailing in the area ofthe implant, it will progressively degrade, over a period of preferablyseveral weeks, months, or years, through molecular breakdown. Thesemolecular separation products and any other metabolites preferablydisplay no or, at worst, only negligible toxicity and the body should beable to metabolize or excrete all or most of them. Polymers, whichcontain no toxic metabolites and can be completely biodegraded andeliminated, are also sometimes referred to as bioresorbable. Thepolymers used in applying this invention are preferably of thebioresorbable type.

It is surprising that, even without the addition of otherpharmaceutically active agents such as growth factors, the varnish-likecoating promotes osteosynthesis (and thus contributory fracture-healing,infection-fighting, and complication-avoiding effect).

The thickness of the varnish-like coating is preferably 50 μm, morepreferably about 30 μm, and most preferably about 20 μm or less. In manycases, the preferred thickness is between 10 and 30 μm and mostdesirably between 10 and 20 μm.

The polymer employed preferably has a glass transition temperature of37° C. (98.6° F.) or higher so as to retain its desired strength in thebody. Polymers with a mean molecular weight of 100 kDa or less arepreferred.

The polymer is preferably selected from the group comprisingpoly-α-hydroxy acids, polyglycols, polytyrosine carbonates, starch,gelatins, cellulose as well as blends and interpolymers containing thesecomponents. Particularly preferred among the poly-α-hydroxy acids arethe polylactides, polyglycol acids, and their interpolymers. One exampleof a suitable polylactide is marketed by Boehringer-Ingelheim under thetrade name R 203. It is a racemic poly-D,L-lactide. This racemiccompound forms an amorphous, varnish-like layer on the surface of theimplant. The formation of crystalline polymer structures in the coatingshould preferably be avoided, which is why an enantiomerically purelactide is preferably avoided. Suitable polytyrosene carbonates includefor instance p(DTE-co-5% PEG 1000 carbonates) and p(DTE-co-26% PEG 20000carbonates). These are copolymers containing the specified amounts ofpolyethylene glycols.

The coating may contain additional pharmaceutically active agents, suchas osteoinductive or biocidal or anti-infection substances. Suitableosteoinductive substances include, for example, growth factors whoseproportion of the total weight of the coating is preferably 0.1 to 10%by weight or, more preferably, 0.5 to 8% by weight and, most desirably,1 to 5% by weight. This weight percentage relates to the net amount ofthe active agent, without counting any pharmaceutical carriersubstances.

The growth factors may be selected from the group of IGF (insulin-likegrowth factors), TGF (transforming growth factors), FGB (fibroblastgrowth factors), EGF (epidermal growth factors), BMP (bone morphogenicproteins) and PDGF (platelet-derived growth factors). These growthfactors are well known and are commercially available. The varnish-likecoating preferably contains the IGF-I or TGF-β growth factors, withparticular preference given to a combination of these two growthfactors.

This invention also relates to a method for producing an implant of thetype described above, which may include the steps of:

-   -   Preparing a dispersion of the biodegradable polymer in an        organic solvent;    -   Applying the dispersion on the surface to be coated; and    -   Allowing the solvent to evaporate.

The term dispersion refers to any given distribution of the polymer inan organic solvent. This may be a chemical solution, a purely physicaldispersion or any intermediate step, especially including for instance,colloidal solutions. The application of the dispersion and theevaporation of the solvent preferably take place at a temperature ofbetween 0 and 30° C. (32-86° F.), and more desirably at a roomtemperature of about 22° C. (72° F.). This so-called cold coating alsoallows for temperature-sensitive components such as certain growthfactors to be applied on the implant together with the polymer. Applyingthe dispersion is performed preferably by immersing the implant in thedispersion. Other ways of applying the coating, for example by brushing,spraying, etc. are also possible. Of course, in addition to the polymer,the dispersion may also contain the aforementioned pharmaceuticallyactive agents such as osteoinductive or biocidal substances.

Most preferably, the solvent is allowed to evaporate in a gasatmosphere, essentially saturated with solvent vapor. To that end, it isdesirable to manipulate the implant that has been immersed in thedispersion, in a closed space whose atmosphere is highlysolvent-saturated. Preferably, this will result in a very slowevaporation of the solvent, and consequently, in a uniform,well-adhering varnish-like coating. The preferred evaporation time isbetween 1 minute and 1 hour, or more preferably 5 to 30 minutes, andmost desirably about 10 minutes. It is also preferred to apply thecoating by incrementally building it up in several thin layers, forexample by repeating the dispersion and the solvent-evaporationprocesses two or more times.

Preferably, a dispersion which is constituted by a colloidal solution ofthe polymer in the solvent may be used. This colloidal solutionpreferably contains colloidal polymer particles between 1 and 1000 nmand preferably less than 400-500 nm in size. For example, this type ofcolloidal solution can be produced by mixing the polymer and thesolvent, then letting it stand for a period of 1 minute to 24 hours,preferably 2 to 24 hours, more preferably 3 to 12 hours, still morepreferably 8 hours, and most desirably about 6 hours. During the mostpreferred period of about 6 hours, polymer colloid particles will formin the desired size range of less than about 500 nm. To separate anyremaining larger polymer particles, the colloidal solution can befiltered prior to its application on the implant, preferably by using amicropore filter whose pore size corresponds to the desired maximum sizeof the colloid particles. Micropore filters are commercially availablewith pore sizes for example of 0.45 or 0.2 μm.

The solvents used are preferably popular organic, nonpolar or weaklypolar solvents. Particular preference may be given to ethyl acetate orchloroform. Prior to its application on the implant, the dispersionpreferably contains an amount of, preferably 20 to 300 mg, and moredesirably 50 to 150 mg, polymer (perhaps including other constituentssuch as osteoinductive or biocidal substances) per ml of solvent.

These and other aspects of the present invention may be more fullyunderstood with reference to the following non limiting examples, whichare merely illustrative of the preferred embodiments of the presentinvention, and are not to be construed as limiting the invention, thescope of which is defined by the appended claims.

Example 1

Method for Making a Bioactive Implant

400 mg PDLLA (poly(D,L) lactide, Resomer R 203 by Boehringer-Ingelheim)is dispersed in 6 ml chloroform at room temperature. If the coating isto contain other osteoinductive or biocidal substances, these are alsoadded to the dispersion, in which case 400 mg is the total combinedweight of the PDLLA and the additives. The dispersion is allowed to sitfor 6 hours until a colloidal solution has formed, which is then passedthrough a sterile microfilter with a pore size of 0.45 μm into a sterilecontainer.

Next, Kirschner wires (1.6 mm in diameter, 3.5 cm long) of titanium andsteel as well as titanium bone nails are immersed in the filteredsolution, whereupon the solvent is allowed to evaporate in a chloroformatmosphere for a period of 10 minutes. This process (coating andevaporation) is repeated once. The implants obtained preferably will becoated with a thin, varnish-like polymer layer about 10 to 20 μm thick.

Example 2

Microbiological Properties of the Coating

After an incubation time of either 6 or 12 weeks, microbiologicalexaminations of titanium Kirschner wires coated with a layer of PDLLAaccording to example 1 revealed no noticeable growth of microorganisms.Additionally, ten implants coated with PDLLA and ten uncoated implantswere each contaminated with staphylococci (KD 10⁵). The coated implantsdisplayed a significantly lower adhesion rate of these microorganisms.

Example 3

Mechanical Strength of the Coating

Twenty titanium and steel Kirschner wires each were weighed and thencoated, as in Example 1, with PDLLA containing 1% methyl violet as colormarker. The wires were implanted in the tibiae of rats. Followingexplantation, the mechanical abrasion of the coating was measured byweighing and by photometric analysis. The highest abrasion rate foundwas 2.9% in the case of titanium wires and 4.6% for steel wires. Rasterelectron micrographs showed that in none of the implants examined hadthe coating been abraded all the way to the metal surface.

Example 4

Method for Making a Bioactive Implant

This example will show the advantages of a colloidal solution for themechanical strength of the coating. 800 mg each of PDLLA R 203 was addedto 2 batches of 6 ml ethyl acetate each. The resulting dispersions wereallowed to sit at room temperature for either 6 or 24 hours respectivelyand were then filtered as in Example 1. The dispersions or solutionsthus obtained were used to coat stents, employing the procedure perExample 1. It should be mentioned that although stents are notorthopaedic implants, they were used only because they are particularlywell suited for elongation tests, and, as a result, for the analysis ofthe mechanical strength of the varnish-like coating. The volume of thecoating was determined by weighing the stents before and after theapplication of the coating. The coated stents were expanded with a PTCAballoon at a pressure of 8 bar (116 psi) using conventional techniques.The expanded stents were weighed again to determine the amount of thecoating material that had peeled off or was lost some other way.

It was found that the stents which were coated with the dispersion thathad stood for 6 hours prior to the filtering had lost an average of 0.8%of their coating while the other stents (which had stood for 24 hours)had a loss of 6.0% by weight. This indicates that for mechanicalstrength of the coating, it is preferable not to produce a completechemical polymer solution in the solvent, but rather, a colloidalsolution with a colloidal particle size of 0.45 μm or less.

Example 5

Stability of the Active Agents Contained in the Coating

To determine the stability of the growth factors (WF) incorporated inthe coating, titanium Kirschner wires were coated with PDLLA as inExample 1, containing the growth factors IGF-I (5% by weight) and TGF-β(1% by weight). The stability (storage life) of the growth factors wasanalyzed after 6 weeks, 6 months and 1 year. After 6 weeks, the loss ineffectiveness was found to be less than 3%. After 6 months, the growthfactors included in the coating were found to be still better than 95.5%effective; and after 1 year better than 93%. This proves that the activeagents, incorporated in the coating as provided for by the invention,retain their biological stability and effectiveness even if the coatedimplant is stored for an extended period of time before it is used.

Example 6

Biodegradation of the PDLLA Coating

Titanium Kirschner wires, coated with PDLLA per Example 1, weresubjected to in-vitro elutriation tests. To simulate in vivo situations,the elutions were passed through a physiological 0.9% NaCl solution at atemperature of 37° C. (98.6° F.) under laminar air-flow conditions.Within 9 weeks about 10% of the PDLLA coating had progressivelydegraded. For an in vivo study of the biodegradation characteristics ofthe PDLLA coating, 10 PDLLA-coated Kirschner wires with a definedcoating volume were implanted in Sprague Dawley rats. After 6 weeks, theimplants were removed and the in vivo degradation of the PDLLA coatingwas determined by measuring the difference between the pre-implantationand the post-explantation weight, as well as the inherent viscosity, andthe molecular weight of the completely separated coating, followed by acomparison with the in vitro data.

As shown in FIG. 1, about 10% of the PDLLA coating had biodegradedwithin 9 weeks. The comparative in vivo measurement shows that at thatpoint in time, the in vitro and in vivo results were fairly identical.

Example 7

Examination of the Release of Active Agents Integrated in the Coating

As in Example 1, titanium Kirschner wires were coated with PDLLA, whichadditionally contained either 5% by weight of IGF-I or 1% by weight ofTGF-β1 or a combination of 5% by weight of IGF-I and 1% by weight ofTGF-β1. The release pattern of the growth factors incorporated in thecoating was analyzed with in vitro elutriation tests. The results areshown in FIG. 2. Within 48 hours, an initial release of growth factorsfrom the coating took place at a rate of 48 to 54%. From there, therelease continued progressively until after 6 weeks, a total of between71 and 78% of the growth-factor inclusions were released.

Ten titanium Kirschner wires, coated with PDLLA and the above-mentionedgrowth factors, were implanted in the tibiae of each of the SpragueDawley rats used. After 42 days, the implants were removed and theresidual concentrations of the growth factor inclusions were measured,using ELISA. As shown in FIG. 2, the in vivo results matched those ofthe in vitro elutriation tests.

Example 8

Osteoinductive Effect of the Implants

In an experiment with animals, tests were conducted on 60 such animals(5-months-old female Sprague Dawley rats). All test animals weresubjected to a standardized fracture of the right tibia. Differentlycoated titanium wires (1.0 mm in diameter) were then implanted in therepositioned tibiae as intramedullary supports.

Depending on the group assignments as specified below 2 mg/kg of arat-specific recombinant growth hormone (r-rGH) or a placebo wassubcutaneously injected daily for a period of time up to 42 days. Atvarious time points (0 d, 4 d, 7 d, 14 d, 21 d, 28 d, 35 d, and 42 d)and after administration of an anaesthetic inhalant, x-rays were takenin two planes, 1.25 ml of blood was taken from each by the retrobulbarmethod (deep-frozen at −80° C. (−112° F.)), and their weight and bodytemperature were measured. On day 42, the fractured and the unfracturedtibiae, along with the periosteum, were separately prepared andsubjected to biomechanical tests (torsional load-torsional stiffness).

Group assignments

-   -   Group I: Fracture of the right tibia—uncoated implant—Systemic        application of a placebo (control group)    -   Group II: Fracture of the right tibia—implant coated with        poly-D,L-lactide 203—Systemic application of a placebo    -   Group III: Fracture of the right tibia—implant coated with        poly-D,L-lactide—Systemic application of (r-rGH)    -   Group IV: Fracture of the right tibia—implant coated with        poly-D,L-lactide and growth factors IGF-I (5%) and TGF-β        (1%)—Systemic application of a placebo    -   Group V: Fracture of the right tibia—implant coated with        poly-D,L-lactide and growth factors IGF-I (5%) and TGF-β        (1%)—Systemic application of (r-rGH)

The coated implants were produced as indicated in Example 1.

Results:

Fracturing

The fracturing model employed lent itself well to the creation of astandardized transverse fracture of the right tibia, without any majordamage to the soft tissue. In 2 out of 60, the tibia fracture wascomminuted; in one, it was helical, requiring premature discontinuation.One animal died in a postoperative examination under anesthesia (32ndday).

Weight and Temperature

In the animals systemically treated with (r-rGH) (Groups III and V),there was no rise in body temperature during the course of the test, incomparison to the animals that had been given a placebo (Groups I, IIand IV), but their body weight increased significantly by 13% (p<0.05).No major differences were found among Groups I, II and IV (placebo) orIII and V (GH).

Biomechanical Test

The data obtained are expressed in absolute values (torsional load) andin percentages (torsional stiffness), as compared to the unfracturedopposite side. The results reveal a significant increase (p<0.05) of themaximum torsional load in Group III, as well as Groups IV and V, ascompared to the systemic application. It appears that the localapplication of growth factors (Group IV) not only leads to a markedlyhigher maximum torsional load, compared to the control group, but onaverage also when compared with the results of the systemic applicationof r-rGH (insignificant). No further increase in the maximum torsionalload was observed as a result of simultaneous administration of r-rGHand the local application of IGF-I and TGF-β. The maximum torsional loadin the group treated with poly-D,L-lactide increased significantly,compared to that of the control group. In terms of torsional stiffness,relative to that of the contralateral tibia, comparable findings weremade. In this case as well, the groups with the local application ofgrowth factors showed the most favorable results. FIG. 9 summarizesthese results.

Example 9

5 months-old female Sprague Dawley rats (n=144) were subjected to astandardized closed fracture of the right tibia using a fracturingmachine; and uncoated versus coated titanium Kirschner wires wereimplanted in the tibiae as intramedullary stabilizers. A comparison wasmade between the following groups:

-   -   Group I: Uncoated implant (control group)    -   Group II: Implant coated with PDLLA 7 203)    -   Group III: Implant coated with PDLLA+r-IGF-I (5%)    -   Group IV: Implant coated with PDLLA+r-IGF-I (5%)+TGF-β1 (1%)

The coated implants were produced as in Example 1. Time-sequentialradiographs were taken in 2 planes (a.-p. and lateral). At time points 0d, 4 d, 7 d, 14 d, 21 d, 28 d, sera were measured, including thesystemic concentration of r-IGF-I and r-TGF-β1 and the body weight andbody temperature were determined. After 4 weeks, the implants wereremoved and the fractured tibiae were biomechanically tested incomparison with the untreated contralateral tibiae. Thehistomorphometric examination (O. Safranin/v. Kossa) of the calli wasquantified by means of an analytical imaging system (Zeiss KS 400).

In the radiographic evaluation, the untreated Group I still showed adistinct fractured dissociation. Groups II and III displayed good callusformation, as compared to the uncoated Group I. In the animals of GroupIV, the fractures had almost completely consolidated (FIG. 3). Comparedto the untreated contralateral tibia, and in a comparison with all othergroups, the biomechanical tests revealed for Group IV a significantlyhigher maximum torsional load and maximum torsional stiffness. Thecombined application of r-IGF-I and r-TGF-β1 produced a substantiallyhigher maximum torsional load and maximum torsional stiffness, comparedto the group treated with IGF-I. The group treated with polylactideshowed a significantly higher maximum torsional load and maximumtorsional stiffness than the untreated Group I (FIG. 4).

The histomorphometric examinations substantiate the radiographic andbiomechanical test results. There were substantially more areas ofconnective tissue cells in Group I than in the treated groups. The grouptreated with PDLLA displayed good callus formation and a pattern ofadvanced callus reconstruction, with a minimal proportion of connectivetissue cells. Group IV displayed an almost completely restored fractureand the highest bone density in the callus. The group treated withpolylactide only also showed a significantly higher bone density in thecallus area, as compared with the control group (FIGS. 5 and 6).

Between the treated and the untreated groups, no changes were evident interms of serum parameters, body weight, or body temperature.

Example 10

12 months-old Yucatan dwarf pigs (n=30) were subjected to a standardizedosteotomy (1 mm gap) of the right tibia which was then intramedullarilystabilized with either coated or uncoated titanium tibia nails andstatically locked. A comparison of the following groups was made:

-   -   Group I: Uncoated implant (control group)    -   Group II: Implant coated with PDLLA 7 203)    -   Group III: Implant coated with PDLLA+r-IGF-I (5%)+TGF-β1 (1%)

The coated implants were produced as in Example 1. Time-sequentialradiographic examinations and serum tests were performed. After 4 weeks,the two tibiae were removed and biomechanically tested. The callusdiameter was measured and the callus volume was determined by theArchimedes principle.

Results:

After 4 weeks, all of the control-group animals showed an incompleteconsolidation of the osteotomy gap. The group treated with polylactideshowed good callus formation. Group III displayed substantially advancedcallus formation (FIG. 7). In Group II, treated with polylactide, andGroup III, additionally treated with growth factors, the callus volumeand callus diameter were significantly greater than in the controlgroup.

Compared to the contralateral tibia, and in comparison with the controlgroup, the group treated with polylactide displayed a considerablyhigher maximum torsional load and maximum torsional stiffness. Theinclusion of growth factors in the polylactide coating produced asignificant augmentation of the maximum torsional load and maximumtorsional stiffness.

Strength of the Intramedullary Support

The standardized explantation of the titanium wires from the tibiae,using a power extractor, required substantially more extractive forcefor explanting the wires coated with IGF-I and TGF-β than those in thecontrol group.

It is evident from Examples 8 to 10 that the use of an implant coatedwith a varnish-like biodegradable polymer coating can significantlyaccelerate the osteosynthesis and thus the healing process of thefracture. This accelerated process has been documented for apolymer-coated implant, without the addition of other osteoinductiveagents. Incorporating growth factors in the coating permits a furtheracceleration of the fracture-healing process, with the combinedapplication of IGF-I and TGF-β being particularly effective.

The examples also show that by means of the method per this invention,it is possible to produce a varnish-like coating, which by virtue of itsphysical structure and mechanical strength clearly distinguishes itselffrom any prior art.

While various descriptions of the present invention are described above,it should be understood that the various features can be used singly orin any combination thereof. Therefore, this invention is not to belimited to only the specifically preferred embodiments depicted herein.

Further, it should be understood that variations and modificationswithin the spirit and scope of the invention may occur to those skilledin the art to which the invention pertains. Accordingly, all expedientmodifications readily attainable by one versed in the art from thedisclosure set forth herein that are within the scope and spirit of thepresent invention are to be included as further embodiments of thepresent invention. The scope of the present invention is accordinglydefined as set forth in the appended claims.

What is claimed is:
 1. An orthopedic implant comprising: (a) a friction surface to slide against bone; (b) a body; and (c) a varnish-like abrasion-resistant coating, wherein said coating comprises a biodegradable polymer having a mean molecular weight of 100 kDa or less; said coating has a thickness of 100 μm or less; said coating is adhesively bonded to the surface of the body by a method, comprising: preparing a dispersion of the biodegradable polymer in an organic solvent; applying the dispersion on the surface; and evaporating the organic solvent in an atmosphere having a controlled amount of organic solvent.
 2. The implant of claim 1, wherein the implant is a fracture-fixation device or endoprosthetic device.
 3. The implant of claim 2, wherein the implant is a fracture-fixation device that is selected from the group consisting of a plate, screw, nail, pin, wire, thread, and cage.
 4. The implant of claim 1, wherein the varnish-like abrasion-resistant coating has a thickness of 50 μm or less.
 5. The implant of claim 4, wherein the varnish-like abrasion-resistant coating has a thickness of 10 to 30 μm.
 6. The implant of claim 1, wherein the biodegradable polymer has a glass transition temperature of more than 37° C. (98.6° F.).
 7. The implant of claim 1, wherein the biodegradable polymer is a poly-α hydroxy acid, polyglycol, polytyrosine carbonate, starch, gelatin, cellulose, or a blend or interpolymer thereof.
 8. The implant of claim 7, wherein the biodegradable polymer is a poly-α hydroxy acid that is polylactide, polyglycol acid, or an interpolymer thereof.
 9. The implant of claim 1, wherein the varnish-like abrasion-resistant coating contains a pharmaceutically active additive.
 10. The implant of claim 9, wherein the pharmaceutically active additive includes an osteoinductive substance.
 11. The implant of claim 10, wherein the osteoinductive substance contains a growth factor.
 12. The implant of claim 11, wherein the growth factor is present in an amount from 0.1 to 10% by weight of the coating.
 13. The implant of claim 11, wherein the growth factor includes at least one of IGF, TGF, FGF, EGF, BMP, and PDGF.
 14. The implant of claim 11, wherein the growth factor is IGF-I, TGF-β, or a mixture thereof.
 15. The implant of claim 14, wherein the varnish-like abrasion-resistant coating contains about 5% by weight of IGF-I and 1% by weight of TGF-β.
 16. The implant of claim 1, wherein the varnish-like abrasion-resistant coating contains at least two layers of the biodegradable polymer.
 17. The implant of claim 1, wherein the body comprises a base material which is not biodegradable.
 18. The implant of claim 17, wherein the base material consists of a metal or an alloy.
 19. The implant of claim 17, wherein the base material is stainless steel, titanium, or a mixture thereof.
 20. The implant of claim 2, wherein the implant is an endoprosthetic device.
 21. An orthopedic implant comprising: a body formed from a biocompatible material; a surface of the body; and a film forming an adhesive bond on the surface by a method, comprising: preparing a dispersion of the biodegradable polymer in an organic solvent; applying the dispersion on the surface; and evaporating the organic solvent in an atmosphere having a controlled amount of organic solvent to adjust a rate of evaporation.
 22. The orthopedic implant of claim 21, wherein the body formed from a biocompatible material includes a body formed from a bioresorbable material.
 23. The orthopedic implant of claim 21, wherein the body formed from a biocompatible material includes a body formed from a non biodegradable material.
 24. The orthopedic implant of claim 21, wherein preparing the dispersion of the biodegradable polymer in the organic solvent includes preparing a colloidal solution of the biodegradable polymer in the organic solvent; letting the colloidal solution stand for between 3 and 12 hours; filtering the colloidal solution to remove particles larger than approximately 500 nm.
 25. The orthopedic implant of claim 21, wherein the film includes a pharmaceutically active additive. 